Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6]([C:8]1[S:12][C:11]([NH2:13])=[N:10][N:9]=1)=[O:7]>C(OCC)(=O)C>[CH3:5][S:6]([C:8]1[S:12][C:11]([N:13]=[C:1]=[O:2])=[N:10][N:9]=1)=[O:7]
Reactant: CS(=O)c1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)c1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-methylsulfinyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[NH:6][N:7]=1.Cl.[N:12]1([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:9][N:4]1[C:3](=[O:10])[C:2]([N:15]2[CH2:16][CH2:17][N:12]([C:18](=[O:19])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:27])[F:28])[CH2:13][CH2:14]2)=[N:7][NH:6][C:5]1=[O:8].[C:20]1([CH3:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: Cl
Product: Cc1ccccc1
Product: Cn1c(=O)[nH]nc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)c1=O
Yield: 27 %

Procedure:
The compound 4 (solid) is prepared from the triazine 2a and the intermediate 6a according to the synthesis method 1 in toluene (yield: 27%).
Reaction SMILES: [ClH:1].C1([C:8]2[CH:23]=[CH:22][C:11]([NH:12][N:13]=NNC3C=CC=CC=3)=[CH:10][CH:9]=2)C=CC=CC=1.C(O)C.[NH4+].[OH-].Cl.[NH:30]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]3[N:49]=[CH:48][NH:47][C:45]3=2)[N:40]=[C:39]([CH3:50])[CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO>[ClH:1].[C:11]1([N:12]=[N:13][C:34]2[CH:35]=[CH:36][C:31]([NH:30][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[C:44]5[N:49]=[CH:48][NH:47][C:45]5=4)[N:40]=[C:39]([CH3:50])[CH:38]=3)=[CH:32][CH:33]=2)[CH:22]=[CH:23][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: c1ccc(NN=NNc2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: Cc1cc(Nc2ccc(N=Nc3ccccc3)cc2)c2c(ccc3nc[nH]c32)n1

Procedure:
A solution of 11.7 g. (0.05 m.) of p-phenylazoaniline hydrochloride in 500 ml. of ethanol was adjusted to pH 7.0 with 28% NH4OH. After the addition of 11 g. (0.05 m.) of the compound of Example I, C., the mixture was refluxed overnight. It was chilled, filtered, washed with ether and airdried to give 22 g. The crude product was recrystalled from MeOH to yield 17 g.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([OH:25])[C:9]=3[C:8]2=[O:26])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:35](Br)[CH:36]=[CH2:37]>CN(C)C=O.C(OC(=O)C)C>[CH2:37]([O:25][C:10]1[C:9]2[C:8](=[O:26])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[C:19](=[O:20])[C:18]=2[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2)[CH:36]=[CH2:35]
Reactant: COCOc1c2c(c(O)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1c2c(c(OCOC)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxymethyl ether 6 (0.0172 g, 0.045 mmol) was dissolved in 1.5 mL dry dimethylformamide (DMF). Ground K2CO3 (0.0186 g, 0.135 mmol) was added, followed by allyl bromide (0.0077 mL, 0.09 mmol). The mixture was stirred at room temperature overnight, then diluted with 100 mL of ethylacetate, washed with saturated NH4Cl solution, dried (MgSO4), and concentrated to give crude 10. The crude product 10 was chromatographed on silica gel, eluting with ethylacetate and hexanes to give white solid allyl, methoxymethyl diether 10: (0.0063 g, 33%). 1H NMR (CDCl3) δ 9.1 (dd, 1H), 8.8 (dd, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 6.1 (m, 1H), 5.8 (s, 2H),5.5 (d, 1H), 5.3 (d, 1H), 5.1 (d, 2H), 4.8 (s, 2H). MS: 423 (M+1); 445 (M+23).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([C:9]([OH:11])=O)[CH2:2]2.S(Cl)(Cl)=O.[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:9]([C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)=[O:11])=[CH:19][CH:18]=1
Reactant: O=C(O)[C@H]1CN2CCC1CC2
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(Br)cc1)[C@H]1CN2CCC1CC2

Procedure:
9.17 g (about 47.8 mmol) of (R)-1-azabicyclo[2.2.2]octane-3-carboxylic acid are heated together with 160 ml of thionyl chloride under reflux for 1 h. The excess thionyl chloride is removed under reduced pressure, and residues are removed by azeotropic distillation together with toluene. The crude acid chloride obtained in this way is stirred together with 8.19 g (47.60 mmol) of 4-bromoaniline and 24.6 ml (190.4 mmol) of N,N-diisopropylethylamine in 59 ml of DMF at RT for 72 h. The solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol/triethylamine 70:30:2). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 5.5 g (37% of theory) of the title compound are obtained. The absolute configuration was assigned by crystal structure analysis of single crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH:29]1([CH2:32][NH2:33])[CH2:31][CH2:30]1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:33][CH2:32][CH:29]3[CH2:31][CH2:30]3)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: NCC1CC1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)NCC2CC2)c1

Procedure:
Example 137 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and 1-cyclopropylmethanamine to give the title compound (0.008 g).
Reaction SMILES: F[C:2]1[C:7]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[O:11][C:10](=[O:20])[NH:9]2)=[CH:6][C:5]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:4][N:3]=1.[OH-:29].[K+].[CH3:31]O>>[F:19][C:15]1[CH:14]=[C:13]([C@H:12]2[O:11][C:10](=[O:20])[NH:9][C@@H:8]2[C:7]2[C:2]([O:29][CH3:31])=[N:3][CH:4]=[C:5]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CO
Reactant: [OH-]
Reactant: O=C1N[C@H](c2cc(C#Cc3ccccc3)cnc2F)[C@@H](c2cccc(F)c2)O1
Agent: [K+]
Product: COc1ncc(C#Cc2ccccc2)cc1[C@H]1NC(=O)O[C@@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4R,5R)-4-(2-fluoro-5-(phenylethynyl)pyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (10 mg, 0.027 mmol) in methanol (0.25 mL) at 0° C. was added a solution of potassium hydroxide (14.9 mg, 0.266 mmol) in methanol (0.25 mL, 6.18 mmol). After 1 h at 0° C., the reaction was allowed to stir at room temperature for 24 h. The reaction was quenched by addition of solid ammonium chloride (30 mg) and concentrated. The resulting residue was dissolved in dichloromethane, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated. The product was purified by Prep HPLC (TFA/MeOH, sunfire column) and concentrated to give 7.7 mg (73%). 1H NMR (CDCl3) δ: 8.38 (d, J=2.1 Hz, 1H), 7.84-7.88 (m, 1H), 7.53-7.58 (m, 2H), 7.43 (td, J=7.9, 5.8 Hz, 1H), 7.36-7.40 (m, 3H), 7.24 (dd, J=7.6, 0.6 Hz, 1H), 7.19 (dt, J=9.4, 2.0 Hz, 1H), 7.09-7.15 (m, 1H), 5.90 (s, 1H), 5.37 (d, J=4.3 Hz, 1H), 4.98 (d, J=4.3 Hz, 1H), 4.00 (s, 3H). 13C NMR (CDCl3) δ: 163.1, 160.1, 158.8, 150.1, 141.1, 137.8, 131.7, 130.7, 128.7, 128.6, 122.7, 121.4, 121.1, 121.1, 116.0, 114.1, 112.8, 91.8, 85.4, 83.1, 58.6, 54.1. Mass spec.: 389.2 (MH)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]([N:33]3[CH2:34][CH2:35][N:30]([C:28]4[S:27][N:26]=[C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[N:29]=4)[CH2:31][CH2:32]3)=[O:18])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc2ncsc2c1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccc2ncsc2c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 20.3 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl 1,3-benzothiazol-6-ylcarbamate (240 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 63.2 mg (20.3%) of the desired product as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][N:9]=1>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: COc1ccc(Br)nc1
Reactant: C1CNCCN1
Product: COc1ccc(N2CCNCC2)nc1
Yield: 25 %

Procedure:
This compound was synthesized from piperazine and 2-bromo-5-methoxypyridine as described for example 39 step 1 (130 mg, yield 25%) as pale yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ 7.87-7.86 (d, J=2.9 Hz, 1H), 7.27-7.23 (dd, J=9.1 Hz, 3.2 Hz, 1H), 6.80-6.77 (d, J=9.2 Hz, 1H), 3.71 (s, 3H), 3.32-3.28 (m, 4H), 2.86-2.83 (m, 4H). MS (ESI) m/z: Calculated for C10H15N3O: 193.12. found: 193.9 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([NH2:16])[C:8]([NH2:17])=[N:7][C:6]=1[CH3:18])[CH3:2].C(O)(=O)C.[N:24]([O-])=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]2[N:16]=[N:24][NH:17][C:8]2=[N:7][C:6]=1[CH3:18])=[O:19])[CH3:2]
Reactant: O=N[O-]
Reactant: CCCCNc1c(N)c(N)nc(C)c1C(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCNc1c(C(=O)OCC)c(C)nc2[nH]nnc12
Reaction time: 8 h

Procedure:
2.66 g. of 5,6-diamino-4-butylamino-2-methylnicotinic acid ethyl ester (0.01 mol.) are dissolved in 20 ml. of acetic acid and 5 ml. of water. The mixture is cooled to 5° with stirring. At this temperature, a solution of 0.9 g. of sodium nitrite in 5 ml. of water is showly added dropwise. Stirring is continued for an additional 8 hours. The solvent is distilled off and the residue treated with 20 ml. of water and extracted three times with 10 ml. portions of chloroform. The organic layers are dried with sodium sulfate, filtered and evaporated. The crystalline 7-butylamino-5-methyl-3H-[1,2,3]-triazolo-[4,5-b]pyridine-6-carboxylic acid ethyl ester remains and is recrystallized from methanol, yield 2.3 g. (83%), m.p. 188°-189°.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:10])[CH2:2]2.[Cl:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C(#N)C>[Cl-:27].[F:26][C:22]1[CH:21]=[C:20]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[O:11][C:9]([CH:3]2[CH:4]3[CH2:5][CH2:6][N+:1]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH2:8][CH2:7]3)[CH2:2]2)=[O:10])[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=C(OC(c1cccc(F)c1)c1cccc(F)c1)C1CN2CCC1CC2
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[N+]12CCC(CC1)C(C(=O)OC(c1cccc(F)c1)c1cccc(F)c1)C2
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
Bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (70 mg, 0.20 mmol, prepared as in example 4) and tert-butyl 2-chloroacetate (31 μl, 0.21 mmol) were dissolved in acetonitrile (3 ml) and stirred at room temperature overnight. Tert-butyl 2-chloroacetate (28 μl, 0.20 mmol) was added again, and the mixture was stirred for additional 24 hours. Acetonitrile was evaporated, and the resulting crude compound was triturated from Et2O and filtered to obtain 3-((bis(3-fluorophenyl)methoxy)carbonyl)-1-(2-tert-butoxy-2-oxoethyl)-1-azoniabicyclo[2.2.2]octane chloride (42.4 mg, racemic mixture).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N(CC)CC)C.[Br:27][C:28]1[S:32][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:29]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:27][C:28]1[S:32][C:31]([S:33]([NH:3][C@@H:4]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])(=[O:35])=[O:34])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Br)s1
Yield: 44 %

Procedure:
To a solution of (R)-benzyl 3-amino-4-(dimethylamino)butanoate dihydrochloride (1 g, 3.2 mmol), triethylamine (1.3 mL, 9.6 mmol) and DMAP (20 mg, 0.16 mmol) in anhydrous CH2Cl2 (25 mL) was added 5-bromothiophene-2-sulfonyl chloride (2.5 g, 9.6 mmol). Methylene chloride (200 mL) was added and the solution was washed with dilute NaOH (10 mL), water (10 mL), dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to give the title compound as a yellow solid (650 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 1H, J=3.8 Hz), 7.41-7.27 (m, 5H), 7.04 (d, 1H, J=3.8 Hz), 5.14-5.07 (m, 2H), 3.87-8.83 (m, 1H), 2.92-2.89 (m, 1H), 2.83-2.78 (m, 1H), 2.69-2.64 (m, 1H), 2.60-2.54 (m, 1H), 2.43 (s, 6H); MS ESI 461.3 [M+H]+, calcd for [C17H21BrN2O4S2]+ 461.00.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:5]2[C:15](=[O:31])[N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=O)[C:4]2=[CH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:5]2[C:15](=[O:31])[N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=[S:41])[C:4]2=[CH:3]1
Reactant: Cn1cc2c(c(-c3ccncc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1cc2c(c(-c3ccncc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=S
Temperature: 110 °C
Reaction time: 12 h
Yield: 39.1 %

Procedure:
To a mixture of 5-methyl-7-(4-pyridyl)-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (50 mg, 0.12 mmol) and Lawesson's reagent (25 mg, 0.06 mmol) in toluene (5 ml) was stirred at 110° C. for 12 hours. The solution was concentrated and the residue was purified by preparative thin-layer chromatography (EA:MeOH=5:1) to give the title compound as a yellow solid (10 mg, 19%).
Reaction SMILES: [Cl:1][C:2]([Cl:37])([Cl:36])[CH2:3][O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23][CH2:24]C2C=CC(C(F)(F)F)=CC=2)=[O:22])[CH:15]=1.Cl[C:39](Cl)(Cl)COC(=O)C1C=CC=CC=1CSC1C=CC=C(CC(O)=O)C=1.[F:64][C:65]([F:76])([F:75])[C:66]1[CH:71]=[CH:70][C:69](C(O)C)=[CH:68][CH:67]=1.C(Cl)Cl>CN(C1C=CN=CC=1)C.CCCCCCC.CCOC(C)=O>[Cl:37][C:2]([Cl:1])([Cl:36])[CH2:3][O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([C:21]([O:23][CH2:24][CH3:39])=[O:22])[C:69]2[CH:68]=[CH:67][C:66]([C:65]([F:64])([F:75])[F:76])=[CH:71][CH:70]=2)[CH:15]=1
Reactant: CC(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Reactant: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(c1ccc(C(F)(F)F)cc1)c1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Yield: 67 %

Procedure:
The titled compound was prepared according to the method described for 2-[3-(4-trifluoromethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid 2,2,2-trichloro-ethyl ester above from 2-(3-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (168 mg, 0.387 mmol), 1-(4-trifluoromethyl-phenyl)-ethanol (88 mg, 0.465 mmol), EDCxHCl (111 mg, 0.581 mmol), DMAP (4.7 mg, 0.039 mmol) and DCM (5 mL). The crude was submitted to flash chromatography using heptane and EtOAc (90/10) as eluent to yield the titled compound (157 mg, 67%) as an oil; 1H NMR (400 MHz, CDCl3): δ 1.52 (d, 3H), 3.59 (dd, 2H), 4.52 (s, 2H), 4.96 (s, 2H), 5.90 (m, 2H), 7.09-7.12 (m, 1H), 7.17-7.23 (m, 4H), 7.30-7.42 (m, 4H), 7.57 (d, 2H), 8.08 (d, 1H); Mass spectrum: M−H+ 604.
Reaction SMILES: [C:1]1([NH:7][S:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[O:10]=[S:8]1(=[O:9])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:23][CH2:22][CH2:21][CH2:20][N:11]1[C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCCN(c2ccccc2)S1(=O)=O
Temperature: 60 °C
Reaction time: 48 h
Yield: 35.8 %

Procedure:
To a solution of tert-butyl N-phenylsulfamoylcarbamate (2.0 g, 7.35 mmol) and 1,4-dibromobutane (1.6 g, 7.35 mmol) in acetone (30 mL) was added Cs2CO3 (7.2 g, 22.05 mmol) and the mixture was stirred at 60° C. for 48 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford tert-butyl 1,1-dioxo-7-phenyl-1λ6,2,7-thiadiazepane-2-carboxylate as a yellow oil (860 mg, 39%). LCMS (ESI): m/z=271.1 [M−56+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[N+:43]([O-])=O.[BH4-].[Na+]>C1C=CC=CC=1.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:43][C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][C:2]=1[Br:1])[CH2:6][O:7][CH:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[CH2:9]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Br)c([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Br)c(N)c2)cc1
Reaction time: 1 h

Procedure:
The solution of 10.8 g of tert-butyl 3-(4-bromo-3-nitrobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 250 ml of benzene is admixed with stirring at 10° C. with the solution of 4.08 g of nickel chloride hexahydrate in 150 ml of benzene. At approx. 5° C., the mixture is admixed with 2.0 g of sodium borohydride in small portions over 1 hour. The reaction mixture is stirred for a further 1 hour, poured onto water (500 ml) and extracted with tert-butyl methyl ether (2×500 ml). The organic phases are washed successively with water (500 ml) and brine (500 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rt=6.03.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].Cl.C(O[CH2:20][CH3:21])(=O)C.[CH2:22]([N:24](CC)CC)C>O1CCCC1.C(N)CC>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:24][CH2:22][CH2:20][CH3:21])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCN
Product: CCCNc1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (11.6 g) in tetrahydrofuran (100 mL), triethylamine (8.4 mL) and propylamine (5.1 mL) were added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, 1.0 mol/L aqueous hydrochloric acid and ethyl acetate were added. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain oily 2-(methylthio)-4-(propylamino)pyrimidine-5-carboxylic acid ethyl ester (A1, 11.7 g).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH3:21])[N:15]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:14]=2[CH:29]=1.[OH-].[Li+]>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([N:15]2[C:14]3[CH:29]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[CH:11]=[CH:12][C:13]=3[N:17]=[C:16]2[S:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=1
Reactant: CCCSc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Product: CCCSc1nc2ccc(OCCCCCC(=O)O)cc2n1-c1ccc(C)cc1

Procedure:
128 mg of 6-[[1-(4-methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]-hexanoic acid methyl ester was reacted with lithium hydroxide according to general operating instructions 3. 98 mg was obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[F-].[K+].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C)C=O>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:6]#[N:7]
Reactant: C1COCCN1
Reactant: Cc1cc(C#N)ccc1Br
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1N1CCOCC1
Temperature: 145 °C
Yield: 11.5 %

Procedure:
To a solution of 4-bromo-3-methylbenzonitrile (11 g, 56 mmol) and potassium fluoride (3.3 g, 56 mmol) in anhydrous N,N-dimethylformamide (150 mL) was added morpholine (15 g, 170 mmol) and the reaction was heated at 145° C. for 4 days. The solvent was evaporated in vacuo and the residue was partitioned between diethyl ether and water. The phases was separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo. Purification on a silica gel column using toluene followed by chloroform as eluents gave 1.3 g (11% yield) of the title compound as white crystals: mp 85-86° C.; EIMS (70 eV) m/z (relative intensity) 202 (71, M+).